Tobacco related lung diseases, including chronic obstructive pulmonary disease (COPD) with and without emphysema, are major causes of lung-related disability and death worldwide. In a longitudinal cohort study, we have shown that approximately one half of subjects with severe COPD had at least one emergency center visit and/or hospital admission for respiratory failure as compared to no need for urgent medical care in normal controls or subjects with mild COPD in 23 months. Surprisingly however, we found similar annual symptomatic respiratory virus infection rates in severe COPD subjects as compared to controls. Thus, although patients with severe COPD have comparable documented viral infections, they still utilize more medical care resources than controls. One possible explanation is that the immune response to the viral infection in patients with COPD differs from that of control groups. In support of this idea, our group has recently shown that the lung-specific immune phenotype of stable ex-smokers with COPD and emphysema is biased towards T helper type I (Th1) immune dysregulation that is not seen in those without the disease. We have also detected significant levels of IL-4, the canonical Th2 cytokine, in bronchoalveolar lavage fluid (BAL) of subjects with COPD exacerbation that required mechanical ventilation while very few subjects in the stable COPD or control groups had detectable levels of this pro-allergenic cytokine in BAL. Based on our previous work and our unpublished preliminary findings, we propose to test the central hypothesis that acute exacerbation in subjects with COPD and emphysema is the result of an aberrant immune response that can contribute to worsening of dyspnea and respiratory failure. In response to this RFA, we will prospectively determine the phenotype of COPD subjects who require frequent hospital and/or urgent clinic visits and determine the immunological basis of the acute worsening of respiratory status that results in hospital admissions and the use of mechanical ventilation. We propose three specific aims that will 1) determine the phenotypic characteristics of subjects with virus associated COPD exacerbations, 2) determine the T cell immune bias in viral and non-viral induced COPD exacerbation, and 3) determine the T cell response to lung antigens in COPD subjects under stable and exacerbated disease conditions.